A potential founder variant inCARMIL2/RLTPRin three Norwegian families with warts, molluscum contagiosum, and T-cell dysfunction

Abstract

BackgroundFour patients from three Norwegian families presented with a common skin phenotype of warts, molluscum contagiosum, and dermatitis since early childhood, and various other immunological features. Warts are a common manifestation of human papilloma virus (HPV), but when they are overwhelming, disseminated and/or persistent, and presenting together with other immunological features, a primary immunodeficiency disease (PIDD) may be suspected.Methods and resultsThe four patients were exome sequenced as part of a larger study for detecting genetic causes of primary immunodeficiencies. No disease‐causing variants were identified in known primary immunodeficiency genes or in other disease‐related OMIM genes. However, the same homozygous missense variant in CARMIL2 (also known as RLTPR) was identified in all four patients. In each family, the variant was located within a narrow region of homozygosity, representing a potential region of autozygosity. CARMIL2 is a protein of undetermined function. A role in T‐cell activation has been suggested and the mouse protein homolog (Rltpr) is essential for costimulation of T‐cell activation via CD28, and for the development of regulatory T cells. Immunophenotyping demonstrated reduced regulatory, CD4+ memory, and CD4+ follicular T cells in all four patients. In addition, they all seem to have a deficiency in IFN γ ‐synthesis in CD4+ T cells and NK cells.ConclusionsWe report a novel primary immunodeficiency, and a differential molecular diagnosis to CXCR4‐,DOCK8‐,GATA2‐,MAGT1‐,MCM4‐,STK4‐,RHOH‐,TMC6‐, and TMC8‐related diseases. The specific variant may represent a Norwegian founder variant segregating on a population‐specific haplotype.

CARMIL family proteins as multidomain regulators of actin-based motility

“…Patients lacked regulatory T-cells and suffered from immunodeficiency syndromes similar to those in patients in the studies discussed earlier (Sorte et al , 2016; Wang et al , 2016; Schober et al , 2017). In T-cells isolated from patients, levels of F-actin at the leading edge were decreased and the microtubule network was disorganized.…”

Functional characterization of the first missense variant in CEP78 , a founder allele associated with cone‐rod dystrophy, hearing loss, and reduced male fertility

“…Leu150 is the first leucine residue of an LRR and the LRR seems to fit the consensus sequence of RNAse inhibitor‐like (RI‐like) class leucine rich repeats (Matsushima et al, 2005). Variants of the first leucine to proline, phenylalanine, or histidine in the repeats of four other LRR proteins have been found to be disruptive and to underlie different diseases, including congenital stationary night blindness ( NYX; MIM# 300278), hereditary bleeding disorder ( GP1BA ; MIM# 606672), and immunodysregulation ( CARMIL2 ; MIM# 610859; Matsushima et al, 2005; Sorte et al, 2016). We used homology modeling and FoldX calculations to predict whether the p.(Leu150Ser) variant can similarly affect the structure or stability of CEP78.…”

Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis

“…Four of the 14 27 and CARMIL2. [28][29][30] For the subject with compound heterozygous variants in both TTC7A and LRBA, it remains unclear whether defects in both of these genes are necessary for development of HLH. For DOCK8, deletion of the 59 portion of the gene was discovered through bioinformatic detection of loss of WES reads and confirmed by array comparative genomic hybridization testing (see Stray-Pedersen et al, 15 Figure E4, Proband 30.1).…”